The overall objective of the proposed project is to understand the control of the heart by the sympathetic nervous system, with emphasis on the processes involved in the regulation of the liberation and dissipation of the neurotransmitter. The cardiac responses to sympathetic neural activity depend in part on the concentration of norepinephrine (NE) in the neuroeffector gaps, which in turn depends on the rates of NE release and removal. In this grant period, the major emphasis will be to define the roles of some of the physical processes (diffusion and bulk transport) involved in the dissipation of NE. Studies will be carried out in anesthetized, open-chest dogs. We will stimulate the cardiac sympathetic nerves, and will measure the chromotropic and inotropic responses of the heart and the rates of NE overflow into the coronary sinus blood. These observations will be made in the presence and absence of cocaine. Complete heart block will be produced, so that the heart rate can be varied over a wide range by artificial pacing. The effects of diffusion on the dissipation of NE will be determined by varying the rate of coronary blood flow. The effects of bulk transport, ascribable to the massaging action of the beating heart, will be determined by varying separately the frequency and the strength of the cardiac contractions. We will also continue our investigations of the factors that govern the neuronal release of NE, especially the presynaptic effects of adenosine in the heart. We will determine the effects of exogenous and endogenous adenosine on the cardiac responses to sympathetic stimulation and on the associated rates of NE overflow into the coronary sinus blood.